Quickly disintegrating solid preparations

ABSTRACT

Quickly disintegrating solid preparations which contain: a) an active ingredient; b) D-mannitol having an average particle size of 30 μm to 300 μm; c) a disintegrating agent; and d) celluloses.

TECHNICAL FIELD

[0001] The present invention relates to solid preparations thatdisintegrate quickly in the presence of saliva or a small amount ofwater in the oral cavity, particularly those useful as intraorallydisintegrating solid preparations.

BACKGROUND ART

[0002] For aged people and children who are difficult to swallow drugs,solid preparations that disintegrate or dissolve quickly in the oralcavity have long been developed. For example, an intraorallydisintegrating tablet preparation is described in the InternationalPublication No. WO93/12769, which is obtained by suspending a drug,lactose, and mannitol in aqueous agar solution, filling the resultingsuspension in a molding pocket or the like, and drying the molding underreduced pressure. This molding shows quick disintegration but is morefragile than usual tablets so that it is readily cracked, chipped, etc.and a long time is required for its production; thus the process forproduction is poor in productivity. In Japanese Patent Laying-OpenNo.6-218028(1994) and Japanese Patent Laying-Open No.8-19589(1996), aprocess for production of a tablet preparation is described, where moistpowder after kneading is filled in the tablet molding well for wetshaping followed by drying. The resulting tablet preparation, beingporous and having a moderate void fraction, shows quick disintegration.However the industrial productivity of this process for production ispoor because a wet material with low fluidity is filled and compressedso that the amount filled in each well varies greatly and a specialdryer is necessary.

[0003] Then a few processes for production of an intraorallydisintegrating tablet preparation by dry tabletting excellent inproductivity have also been reported. For example, a process forproduction of an intraorally disintegrating tablet preparation by drytabletting using a saccharide with a good moldability and a saccharidewith a poor moldability in combination is described in the InternationalPublication No. WO95/20380. Also a process for production of anintraorally disintegrating tablet preparation by dry tabletting usinggranules obtained by wet or dry granulation using an excipient anderythritol, a sugar alcohol, in combination is described in theInternational Publication No. WO98/02185.

[0004] In addition, a process for production of a tablet preparationthat disintegrates quickly in the oral cavity, by combining a saccharideor a sugar alcohol having a mean particle diameter of not more than 30μm, an active ingredient, and a disintegrating agent is described in theInternational Publication No. WO97/47287. According to this process, themolding obtained by pulverization of a saccharide or a sugar alcohol,such as D-mannitol or lactose, followed by addition of a disintegratingagent, etc. and compression molding shows quick disintegration, whereaswhen coarse particles of a saccharide (lactose, mean particle diameterof 80 μm) or a sugar alcohol (D-mannitol, mean particle diameter of 60μm) before pulverization are used, molding is difficult under a lowtabletting pressure and even the molding obtained under a hightabletting pressure does not show a sufficient mechanical hardness.

[0005] D-mannitol is known to produce a very high friction (binding) atthe surface of the mortar wall during compression molding. In addition,pulverization is undesirable not only because it strengthens thefriction at the surface of the mortar wall but also from the viewpointof handling because it reduces fluidity during the production of thetablet preparation (Summary of lectures at the 14^(th) Symposium onParticulate Preparations and Designs, p.115 (1997), Handbook ofPharmaceutical Excipients 2^(nd) Ed., p.294 (1994), The PharmaceuticalPress).

DISCLOSURE OF THE INVENTION

[0006] The inventors have conducted extensive studies on intraorallydisintegrating tablet preparations that can be industrially producedwith common installations without requiring any special manufacturingtechnique. As the result of the studies, the inventors found that anintraorally disintegrating tablet preparation that has a practically notproblematic hardness, disintegrates quickly, and has no problem inproductivity can be obtained by dry tabletting even under a lowcompression pressure when an active ingredient is combined with arelatively coarse powder of a saccharide or a sugar alcohol, adisintegrating agent, and a cellulose compound. As a result of furtherstudies, the inventors have completed the present invention. That is,the invention relates to:

[0007] (1) a quickly disintegrating solid preparation comprising a) anactive ingredient, b) a saccharide or a sugar alcohol with the meanparticle diameter of 30 μm to 300 μm (not less than 30 μm and not more300 μm), c) a disintegrating agent, and d) a cellulose compound;

[0008] (2) the preparation according to the above-mentioned (1), whereinthe preparation is an intraorally quickly disintegrating solidpreparation;

[0009] (3) the preparation according to the above-mentioned (1), whereinthe preparation is a tablet preparation;

[0010] (4) the preparation according to the above-mentioned (1), wherein40 to 95 parts of a saccharide or a sugar alcohol is contained in 100parts of the solid preparation by weight;

[0011] (5) the preparation according to the above-mentioned (1), wherein0.5 to 15 parts of a disintegrating agent is contained in 100 parts ofthe solid preparation by weight;

[0012] (6) the preparation according to the above-mentioned (1), wherein0.5 to 40 parts of a cellulose compound is contained in 100 parts of thesolid preparation by weight;

[0013] (7) the preparation according to the above-mentioned (1), whereinthe saccharide is one or more saccharides selected from the groupconsisting of glucose, fructose, lactose, sucrose, and trehalose;

[0014] (8) the preparation according to the above-mentioned (1), whereinthe saccharide is lactose;

[0015] (9) the preparation according to the above-mentioned (1), whereinthe sugar alcohol is one or more sugar alcohols selected from the groupconsisting of D-mannitol, erythritol, xylitol, maltitol, and sorbitol;

[0016] (10) the preparation according to the above-mentioned (1),wherein the sugar alcohol is D-mannitol;

[0017] (11) the preparation according to the above-mentioned (1),characterized in that D-mannitol with the mean particle diameter of 30μm to 300 μm is used as the saccharide or sugar alcohol with the meanparticle diameter of 30 μm to 300 μm;

[0018] (12) the preparation according to the above-mentioned (1),wherein the disintegrating agent is one or more disintegrating agentsselected from the group consisting of carmellose calcium,carboxymethylstarch sodium, croscarmellose sodium, and crospovidone;

[0019] (13) the preparation according to the above-mentioned (1),wherein the cellulose compound is one or more substances selected fromthe group consisting of crystalline cellulose, powder cellulose, lowsubstituted hydroxypropylcellulose, and carmellose;

[0020] (14) the preparation according to the above-mentioned (1),wherein the active ingredient is manidipine hydrochloride;

[0021] (15) the preparation according to the above-mentioned (1),wherein the active ingredient is voglibose;

[0022] (16) the preparation according to the above-mentioned (1),wherein the active ingredient is candesartan cilexetil;

[0023] (17) the preparation according to the above-mentioned (1),wherein the active ingredient is pioglitazone hydrochloride;

[0024] (18) the process for production of the preparation according tothe above-mentioned (1), characterized in that a mixture containing a)an active ingredient, b) a saccharide or sugar alcohol with the meanparticle diameter of 30 μm to 300 μm (not less than 30 μm and not morethan 300 μm), c) a disintegrating agent, and d) a cellulose compound ismolded by compression;

[0025] (19) a quickly disintegrating solid preparation containing a) anactive ingredient, b-1) a saccharide or sugar alcohol with the meanparticle diameter of 5 μm to below 90 μm (not less than 5 μm and below90 μm), b-2) a saccharide or a sugar alcohol with the mean particlediameter of 90 μm to 500 μm (not less than 90 μm and not more than 500μm), c) a disintegrating agent, and d) a cellulose compound;

[0026] (20) the preparation according to the above-mentioned (19),containing 0.1 to 10 parts of the ingredient b-2) per 1 part of theingredient b-1) by weight;

[0027] (21) the preparation according to the above-mentioned (19),characterized in that a mixture of the ingredient b-1) and theingredient b-2) as the ingredient b-1) and the ingredient b-2);

[0028] (22) the preparation according to the above-mentioned (21),wherein the mean particle diameter of the mixture is 30 μm to 300 μm(not less than 30 μm and not more than 300 μm);

[0029] (23) the preparation according to the above-mentioned (19),wherein the mean particle diameter of the ingredient b-1) is 30 μm tobelow 90 μm (not less than 30 μm and below 90 μm);

[0030] (24) the preparation according to the above-mentioned (19),wherein the mean particle diameter of the ingredient b-1) is 35 μm to 80μm (not less than 35 μm and not more than 80 μm);

[0031] (25) the preparation according to (19), wherein the mean particlediameter of the ingredient b-2) is 90 μm to 300 μm (not less than 90 μmand not more than 300 μm);

[0032] (26) the preparation according to the above-mentioned (19),wherein the mean particle diameter of the ingredient b-2) is 90 μm to200 μm (not less than 90 μm and not more than 200 μm);

[0033] (27) the preparation according to the above-mentioned (19),wherein the saccharide is one or more saccharides selected from thegroup consisting of glucose, fructose, lactose, sucrose, and trehalose;

[0034] (28) the preparation according to the above-mentioned (19),wherein the saccharide is lactose;

[0035] (29) the preparation according to the above-mentioned (19),wherein the sugar alcohol is one or more sugar alcohols selected fromthe group consisting of D-mannitol, erythritol, xylitol, maltitol, andsorbitol;

[0036] (30) the preparation according to the above-mentioned (19),wherein the sugar alcohol is D-mannitol;

[0037] (31) the preparation according to the above-mentioned (19),characterized in that D-mannitol with the mean particle diameter of 30μm to 90 μm and D-mannitol with the mean particle diameter of 90 μm to300 μm are used as the ingredient b-1) and the ingredient b-2),respectively;

[0038] (32) the process for production of a preparation according to theabove-mentioned (19), characterized in that a mixture containing a) anactive ingredient, b-1) a saccharide or a sugar alcohol with the meanparticle diameter of 5 μm to below 90 μm (not less than 5 μm and below90 μm), b-2) a saccharide or a sugar alcohol with the mean particlediameter of 90 μm to 50 μm (not less than 90 μm and not more than 500μm), c) a disintegrating agent, and d) a cellulose compound is molded bycompression; etc.

[0039] Active ingredients used in the present invention may be in anyform, i.e. solid, crystal, oil, or solution, and one or more agentsselected from the group consisting of, for example, alimentaryroborants, antipyretic analgesic antiphlogistics, psychotropic agents,anxiolytics, anti-depressants, hypnotic sedatives, antispasmodics,central nervous system acting drugs, cerebral metabolism improvingagents, cerebral circulation improving agents, antiepileptics,sympathomimetics, digestives, antacids, antiulcer agents, antitussiveexpectorants, antiemetics, respiratory stimulants, bronchodilators,antiallergic agents, dental stomatic agents, anti-histamines, cardiacs,antiarrhythmic agents, diuretics, hypotensive agents, angiotonics,coronary vasodilators, peripheral vasodilators, antihyperlipemic drugs,cholagogues, antibiotics, chemotherapeutics, antidiabetic agents,osteoporosis treating drugs, antirheumatics, skeletal muscle relaxants,antispasmodic drugs, hormone drugs, alkaloid narcotics, sulfa drugs,gout treating agents, anticoagulants, antineoplastic agents, and thelike are used.

[0040] Alimentary roborants include vitamins such as vitamin A, vitaminD, vitamin E (d-α-tocopherol acetate, etc.), vitamin B1 (dibenzoylthiamine, fursultiamine hydrochloride, etc.), vitamin B2 (riboflavinbutyrate, etc.), vitamin B6 (pyridoxine hydrochloride, etc.), vitamin C(ascorbic acid, sodium L-ascorbate, etc.), and vitamin B12(hydroxocobalamin acetate, cyanocobalamin, etc.), minerals such ascalcium, magnesium, iron, etc., protein, amino acids, oligosaccharides,crude drugs, and the like.

[0041] Antipyretic analgesic antiphlogistics include aspirin,acetaminophen, ethenzamide, ibuprofen, diphenhydramine hydrochloride,chlorpheniramine dl-maleate, dihydrocodeine phosphate, noscapine,methylephedrine hydrochloride, phenylpropanolamine hydrochloride,caffeine, anhydrous caffeine, serrapeptase, lysozyme chloride,tolfenamic acid, mefenamic acid, diclofenac sodium, flufenamic acid,salicylamide, aminopyrine, ketoprofen, indometacin, bucolome,pentazocine, and the like.

[0042] Psychotropic agents include chlorpromazine, reserpine, and thelike. Anxiolytics include alprazolam, chlordiazepoxide, diazepam, andthe like. Antidepressants include imipramine, maprotillinehydrochloride, amphetamine, and the like. Hypnotic sedatives includeestazolam, nitrazepam, diazepam, perlapine, phenobarbital sodium, andthe like. Antispasmodics include scopolamine hydrobromide,diphenhydramine hydrochloride, papaverine hydrochloride, and the like.Central nervous system acting agents include citicoline, and the like.Cerebral metabolism improving agents include meclofenoxatehydrochloride, and the like. Cerebral circulation improving agentsinclude vinpocetine, and the like. Antiepileptics include phenytoin,carbamazepine, and the like. Sympathomimetics include isopreterenolhydrochloride, and the like.

[0043] Digestives include stomachic digestives such as diastase,saccharated pepsin, scopolia extract, cellulase AP3, lipase AP, cinnamonoil, etc., and drugs for controlling intestinal function such asberberine chloride, antibiotics-resistant lactic acid bacteriae,lactobacillus bifidus, etc. Antacids include magnesium carbonate, sodiumbicarbonate, magnesium aluminometasillicate, synthetic hydrotalcite,precipitated calcium carbonate, magnesium oxide, and the like.Anti-ulcer agents include lansoprazole, omeprazol, rabeprazole,famotidine, cimetidine, ranitidine hydrochloride, and the like.

[0044] Antitussive expectorants include chloperastine hydrochloride,dextromethorphane hydrobromide, theophylline, potassiumguaiacolsulfonate, guaifenesin, codeine phosphate, and the like.Antiemetics include difenidol hydrochloride, metoclopramide, and thelike. Respiratory stimulants include levallorphan tartrate, and thelike. Bronchodilators include theophylline, salbutamol sulfate, and thelike. Antiallergic agents include amlexanox, seratrodast, and the like.

[0045] Dental stomatic agents include oxytetracycline, triamcinoloneacetonide, chlorhexidine hydrochloride, lidocaine, and the like.

[0046] Antihistamines include diphenhydramine hydrochloride,promethazine, isothipendyl hydrochloride, chlorpheniramine dl-maleate,and the like.

[0047] Cardiacs include caffeine, digoxin, and the like. Antiarrhythmicagents include procainamide hydrochloride, propranolol hydrochloride,pindolol, and the like. Diuretics include isosorbide, furosemide,hydrochlorothiazide, and the like. Hypotensive agents include deraprilhdyrochloride, captopril, hydraladine hydrochloride, labetalolhydrochloride, manidipine hydrochlorodie, candesartan cilexetil,methyldopa, perindopril erbumine, and the like. Angiotonics includephenylepherine hydrochloride, and the like. Coronary vasodilatorsinclude carbocromen hydrochloride, molsidomine, verapamil hydrochloride,and the like. Peripheral vasodilators include cinnarizine, and the like.

[0048] Antihyperlipemic agents include cerivastatin sodium, simvastain,pravastatin sodium, atorvastatin calcium hydrate, and the like.

[0049] Cholagogues include dehydrocholic acid, trepibutone, and thelike.

[0050] Antibiotics include cefems such as cefalexin, cefaclor,amoxicillin, pivmecillinam hydrochloride, cefotiam hexetilhydrochloride, cefadroxil, cefixime, cefditoren pivoxil, cefterampivoxil, cefpodoxime proxetil, etc., synthetic ones such as ampicillin,ciclacillin, nalidixic acid, enoxacin, etc., monobactams such ascarumonam sodium, penems, carbapenems, and the like.

[0051] Chemotherapeutics include sulfamethizole, and the like.

[0052] Antidiabetic agents include tolbutamide, voglibose, pioglitazonehydrochloride, glibenclamide, troglitazone, and the like.

[0053] Osteoporosis treating drugs include ipriflavone, and the like.

[0054] Skeletal muscle relaxants include methocarbamol, and the like.

[0055] Antispasmodic drugs meclizine hydrochloride, dimenhydrinate, andthe like.

[0056] Antirheumatics include methotrexate, bucillamine, and the like.

[0057] Hormone drugs include liothyronine sodium, dexamethasonephosphate, predonisolone, oxendolone, leuprorelin acetate, and the like.

[0058] Alkaloid narcotics include opium, morphine hydrochloride, ipecac,oxycodone hydrochloride, opium alkaloids hydrochloride, cocainehydrochloride, and the like.

[0059] Sulfa drugs include sulfisomidine, sulfamethizole, and the like.

[0060] Gout treating drugs include allopurinol, colchicine, and thelike.

[0061] Anticoagulants include dicoumarol, and the like.

[0062] Antineoplastic drugs include 5-fluorouracil, uracil, mitomycin,and the like.

[0063] Among these, manidipine hydrochloride, voglibose, candesartancilexetil, pioglitazone hydrochloride, etc., particularly manidipinehydrochloride, are used preferably.

[0064] The active ingredient may be the one diluted with a diluent usedgenerally in the fields of medicine and foods. An active ingredientafter treatment for masking the bitterness of the active ingredient mayalso be used.

[0065] The amount of the active ingredient varies depending on thenature and dose of the active ingredient, and is 0.01 to 40 parts,preferably 0.01 to 20 parts, per 100 parts by weight of the solidpharmaceutical preparation of the invention.

[0066] Saccharides used in the invention include glucose, fructose,lactose, sucrose, trehalose, and the like, among which lactose is usedpreferably.

[0067] Sugar alcohols used in the invention include D-mannitol,erythritol, xylitol, maltitol, sorbitol, and the like, among whichD-mannitol is used preferably.

[0068] One or more saccharides or one or more sugar alcohols may be usedin combination, or a combination of a saccharide and a sugar alcohol maybe used.

[0069] The mean particle diameter of the saccharide or the sugar alcohol(preferably the sugar alcohol, or more preferably D-mannitol) is 30 to300 μm (measured by, for example, the laser diffraction particle sizeanalyzer, SYMPATEC Co.: HELOS & RODOS, etc.), preferably above 30 μm,more preferably 31 μm or more, and further more preferably 35 to 200 μm.Saccharides or sugar alcohols of such a particle size are commerciallyavailable (Lactose 100M and Lactose 200M of DMV, granulated powderlactose Dilactose R and Dilactose S of Freund Industry Co., Ltd.,Tablettose and Flowlac 100 of Meggle Japan, Mannit S and Marinecrystalof Towa Chemical Industry Co., Ltd., 1.05980 of Merck Co., Mannidex ofCerestar Japan, Ltd., Trehalose P of Asahi Chemical Industry Co., Ltd.,Sorbitol DP-50M and Amalty MR-50 of Towa Chemical Industry Co., Ltd.,Pure Fructose S of Kato Kagaku, and the like). Saccharides and sugaralcohols with the mean particle diameter of 5 to 30 μm are commerciallyavailable (Granulac 230 and Solvolac 400 of Meggle Japan, Mannit P,Xylit P, and Amalty MR-100 of Towa Chemical Industry Co., Ltd.,Erythritol (fine powder) of Nikken Chemicals Co., Ltd., and the like).Saccharides and sugar alcholos with the mean particle diameter of 200 to500 μm are commercially available (Sachelac 80 of Meggle Japan,Trehalose G and Xylitol XC of Asahi Chemical Industry Co., Ltd.,Erythritol of Nikken Chemicals Co., Ltd., Anhydrous crystalline glucoseTDA-S and Hydrated crystalline glucose TDH of San-ei Sucrochemical Co.,Ltd., and the like). In addition, saccharides and sugar alcohols withthe mean particle diameter of not less than 500 μm are commerciallyavailable (Prismalac 40 of Meggle Japan, Pure Fructose of Kato Kagaku,Amalty MR-20 and Sorbitol DP-10M of Towa Chemical Industry Co., Ltd.,and the like). A saccharide or sugar alcohol with the necessary meanparticle diameter may be obtained by a method such as pulverization fromthe commercially available product. Pulverization is performed by usinga cutter mill, jet mill, hammer mill, or the like.

[0070] A saccharide or sugar alcohol with the mean particle diameter of5 μm to below 90 μm (preferably 30 to below 90 μm) to strengthen themolding may be combined with a saccharide or sugar alcohol with the meanparticle diameter of 90 μm to 500 μm (preferably 90 μm to 300 μm toincrease fluidity during manufacturing. In combination of a fine powderof a saccharide or sugar alcohol with the mean particle diameter of 5 μmto below 90 μm (preferably 30 to below 90 μm, more preferably 35 to 80μm) with a coarse powder of a saccharide or sugar alcohol with the meanparticle diameter of 90 μm to 500 μm (preferably 90 μm to 300 μm, morepreferably 90 to 200 μm), it is recommendable to use one part of a finepowder of a saccharide or sugar alcohol with 0.1 to 10 parts, preferably0.2 to 5 parts, of a coarse powder of a saccharide or sugar alcohol byweight. Particularly when the active ingredient is manidipinehydrochloride, it is recommendable to use one part of a fine powder of asaccharide or sugar alcohol usually with 0.2 to 3.5 parts, preferablywith 0.3 to 2.5 parts, of a coarse powder of a saccharide or sugaralcohol by weight.

[0071] In combination of a fine powder of a saccharide or sugar alcoholwith a coarse powder of a saccharide or sugar alcohol, one or moresaccharides or one or more sugar alcohols may be combined, or a finepowder of a saccharide or sugar alcohol may be combined with a coarsepowder of the same or a different saccharide or sugar alcohol. Inaddition, a mixture obtained by mixing a fine powder of a saccharide orsugar alcohol with a coarse powder of a saccharide or sugar alcohol maybe molded into a quickly disintegrating solid preparation of theinvention, or a fine powder of a saccharide or sugar alcohol and acoarse powder of a saccharide or sugar alcohol are divided into two ormore groups to prepare granules, followed by molding into the quicklydisintegrating solid preparation of the invention.

[0072] When the mixture of a fine powder of a saccharide or sugaralcohol with a coarse powder of a saccharide or sugar alcohol is used asthe starting material, the mixture has desirably two or more peaks inthe particle size distribution and the mean particle diameter of themixture is desirably 30 μm to 300 μm.

[0073] A desirable combination of a fine powder of a saccharide or sugaralcohol with a coarse powder of a saccharide or sugar alcohol isexemplified by the mixture of D-mannitol with the mean particle diameterof 30 μm to below 90 μm with D-mannitol with the mean particle diameterof 90 μm to 300 μm.

[0074] The amount of a saccharide or sugar alcohol used is 40 to 95parts, preferably 50 to 90 parts, per 100 parts of the solidpharmaceutical preparation by weight.

[0075] Disintegrating agents used include carmellose calcium,carboxymethyl starch sodium, croscarmellose sodium, crospovidone, andthe like, and 0.5 to 15 parts, preferably 1 to 10 parts, thereof is usedper 100 parts of the solid pharmaceutical preparation by weight.

[0076] Disintegrating agents are exemplified by Crospovidone[manufactured by ISP Inc. (USA), BASF (Germany)], Croscarmellose Sodium(FMC- Asahi Chemical Industry Co., Ltd.), Carmellose Calcium (GotokuYakuhin Co., Ltd.), and Carboxymethylstarch Sodium (Matsutani KagakuCo., Ltd., Kimura Sangyo Co., Ltd., etc.).

[0077] The crospovidone product may be any cross-linked polymer that is1-ethenyl-2-pyrrolidinone homopolymer, and usually a crospovidoneproduct having a molecular weight of 1,000,000 or more is used. Examplesof commercially available crospovidone products are Cross-linkedPovidone, Kollidon CL [manufactured by BASF (Germany)], Polyplasdone XL,Xl -10, and INF-10 [manufactured by ISP Inc. (USA)].

[0078] Cellulose compounds used are crystalline cellulose, powdercellulose, low substituted hydroxypropylcellulose, carmellose, and thelike, and 0.5 to 40 parts, preferably 1 to 20 parts, thereof is used for100 parts of the solid pharmaceutical preparation by weight.

[0079] Examples of crystalline cellulose products are CEOLUS KG801,Avicel PH101, PH102, PH301, PH302, and PH-F20, Avicel RC-A591NF (allmanufactured by Asahi Chemical Industry Co., Ltd.), and the like,including also fine crystalline cellulose.

[0080] Examples of low substituted hydroxypropylcellulose products arelow substituted hydroxylpropylcellulose of which content ofhydroxypropoxyl group is 5 to 16% by weight such as Low SubstitutedHydroxypropylcellulose LH11, LH21, LH31, LH22, LH32, LH20, LH30, LH32,and LH33 (all manufactured by Shin-Etsu Chemical Co., Ltd.), and thelike. These are commercially available. Low substitutedhydroxypropylcellulose can be produced by a publicly known procedure,for example the procedure described in Patent Gazette No.57-53100(1982),or a similar procedure.

[0081] Active ingredients, disintegrating agents, and cellulosecompounds may be used in combination of one or more of each.

[0082] The preparation of the invention may contain a starch product asan excipient such as corn starch, potato starch, wheat starch, ricestarch, partially gelatinized starch, gelatinized starch, porous starch,and the like, and various additives used for production of generalpharmaceutical preparations, in their respective suitable amounts,unless they interfere with the effect of the invention. Such additivesinclude excipients, binders, sour agents, foaming agents, artificialsweeteners, flavoring agents, lubricants, colorants, stabilizers,pH-modifiers, surfactants, and the like.

[0083] Excipients include inorganic excipients such as anhydrous calciumphosphate, precipitated calcium carbonate, calcium silicate, lightanhydrous silicic acid, and the like.

[0084] Binders include hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, powdered acacia,gelatin, pullulan, and the like.

[0085] Sour agents include citric acid, tartaric acid, malic acid,ascorbic acid, and the like.

[0086] Foaming agents include sodium bicarbonate, sodium carbonate, andthe like. Sweeteners include saccharin sodium, dipotassiumglycylrrhizinate, aspartame, stevia, thaumatin, and the like.

[0087] Flavoring agents include lemon oil, orange oil, menthol, and thelike.

[0088] Lubricants include magnesium stearate, sucrose esters of fattyacid, polyethyleneglycol, talc, stearic acid, sodium stearylfumarate,and the like.

[0089] Colorants include those for food such as Food Yellow No.5, FoodRed No.2, Food Blue No.2, and the like, food lake colorants, ferricoxide, and the like.

[0090] Stabilizers include disodium edetate, tocopherol, cyclodextrin,and the like.

[0091] pH-Modifiers include citrates, phosphates, carbonates,tartarates, fumarates, acetates, amino acid salts.

[0092] Surfactants include sodium lauryl sulfate, polysorbate 80,hydrogenated oil, polyoxyethylene(160)polyoxypropylene(30)glycol, andthe like.

[0093] The particle diameter of these substances is not particularlylimited, but the particle diameter is preferably not more than 500 μmnot to cause rough feeling in the mouth. These excipients may be usedseparately or in combination of two or more thereof.

[0094] A fine granular nucleus may be used for manufacturing of thesolid preparation of the invention, and such a nucleus may be coatedwith active ingredients and additives etc. followed by further coatingby a publicly known procedure for masking of the taste/odor, for entericcoating, for making the preparation into a sustained release form, andfor other purposes.

[0095] The solid preparation of the invention can be produced either bycompression molding of a mixture comprising a) an active ingredient, b)a saccharide or sugar alcohol with the mean particle diameter of 30 μmto 300 μm, c) a disintegrating agent, and d) a cellulose compound, or bycompression molding of a mixture comprising a) an active ingredient,b-1) a saccharide or sugar alcohol with the mean particle diameter of 5μm to below 90 μm, b-2) a saccharide or sugar alcohol with the meanparticle diameter of 90 μm to 500 μm, c) a disintegrating agent, and d)a cellulose compound.

[0096] The procedures for production by dividing the starting materialsinto two groups are exemplified by:

[0097] [1] compression molding by mixing a group comprising a) an activeingredient, b-1) a saccharide or sugar alcohol with the mean particlediameter of 5 μm to below 90 μm, c) a disintegrating agent, and d) acellulose compound, and a group comprising b-2) a saccharide or sugaralcohol with the mean particle diameter of 90 μm to 500 μm, c) adisintegrating agent, and d) a cellulose compound, followed by additionof a fluidizing agent, lubricant, sweetener, and/or the like in theirrespective suitable amounts, as needed;

[0098] [2] compression molding by mixing a group comprising a) an activeingredient, b-1) a saccharide or sugar alcohol with the mean particlediameter of 5 μm to below 90 μm, and c) a disintegrating agent, and agroup comprising b-2) a saccharide or sugar alcohol with the meanparticle diameter of 90 μm to 500 μm, c) a disintegrating agent, and d)a cellulose compound, followed by addition of a cellulose compound,fluidizing agent, lubricant, sweetener, and/or the like in theirrespective suitable amounts as needed;

[0099] [3] compression molding by mixing a group comprising a) an activeingredient, b-1) a saccharide or sugar alcohol with the mean particlediameter of 5 μm to below 90 μm, b-2) a saccharide or sugar alcohol withthe mean particle diameter of 90 μm to 500 μm, c) a disintegratingagent, and d) a cellulose compound as needed, and a group comprisingb-1) a saccharide or sugar alcohol with the mean particle diameter of 5μm to below 90 μm, b-2) a saccharide or sugar alcohol with the meanparticle diameter of 90 μm to 500 μm, c) a disintegrating agent, and d)a cellulose compound, followed by addition of a cellulose compound,fluidizing agent, lubricant, sweetener, and/or the like in theirrespective suitable amounts as needed.

[0100] The concrete procedures for production include the procedure thatan active ingredient and the raw materials of the preparation are mixedin a mixer followed by immediate tabletting. Also the procedure that thematerials are dry compressed into tablets by the slugging method orroller-compacter method, the procedure for production of granules fortablets by dry tabletting using water, acetone, ethyl alcohol, propylalcohol, or a mixture thereof, in which a binder, if necessary, has beendispersed or dissolved, and the procedure for production of granules fortablets after dividing the materials into two or more groups may beapplicable. For production of tablets from granules for tablets, acellulose compound, a disintegrating agent, a fluidizing agent, alubricant, a flavoring agent, a sweetener, and the like may be mixed asneeded.

[0101] Tablets are molded by using, for example, a single tablettingmachine, rotary tabletting machine, and the like. Pressure fortabletting is usually 2.5 to 30 kN/cm². The shape of the solidpreparation of the invention is not particularly restricted; the tabletmay be round, caplet, doughnut, oblong, etc. or a multilayer tablet, adry-coated tablet, or the like, and may be covered by coating. Thetablet may have marks and letters for identification, and a nick on thesurface.

[0102] The resultant quickly disintegrating solid preparation,preferably intraorally quickly disintegrating solid preparation, morepreferably, intraorally quickly disintegrating tablet of the inventionis quickly disintegrated in the oral cavity and has an adequatehardness. It is excellent also in productivity.

[0103] Namely, the time required for intraoral disintegration ordissolution (the time till the tablet is completely disintegrated by theaction of the saliva in the oral cavity of healthy adult men and women)of the intraorally quickly disintegrating tablet of the invention variesdepending to the size and thickness of the tablet, being normally 5 to90 seconds, preferably about 5 to 60 seconds. The hardness (measured bythe tablet hardness meter) is normally 10 to 200N, preferably about 10to 150 N.

[0104] Therefore the intraorally disintegrating tablet of the invention,like the conventional pharmaceutical preparations containing activeingredients, can be used for treatment and prevention of variousdiseases as a tablet easy to be taken by patients, aged people, andchildren who are difficult to swallow the medicine, and as a safepreparation in emergency for general adult people, and is excellent inlong-term storage and stability.

[0105] The preparation may be orally taken without being disintegratedin the oral cavity, or taken with water. The preparation may also beorally taken after being dissolved in water in a cup or the like.

THE BEST MODE FOR CARRYING OUT THE INVENTION

[0106] The invention is explained in more detail with the followingExamples and Comparative Examples, though these Examples do not limitthe invention.

EXAMPLES

[0107] The tablet preparations obtained in the Examples and in theComparative Examples were subjected to the test methods described belowfor measurement of the hardness and the intraoral disintegration time.Also productivity was assessed based on the observation of fluidity,binding property, and adhesion of powder to the surface of the punchduring production of the tablet.

(1) Hardness Test

[0108] Hardness was measured with the tablet hardness meter (ToyamaSangyo Co., Ltd.). Hardness of each of 5 or 10 tablets was measured, andexpressed in the mean of the measurements.

(2) Intraoral Disintegration Time

[0109] The time till disintegration of the tablet in the presence ofsaliva alone in the oral cavity was measured in 3 healthy adult men (35,49, and 51 years old).

Example 1

[0110] A 40 g portion of manidipine hydrochloride, 303.4 g of D-mannitol(Towa Chemical Industry Co., Ltd.: Mannit S, mean particle diameter of130 μm), 50 g of crystalline cellulose (Asahi Chemical Industry Co.,Ltd.), 50 g of corn starch (Japan Corn Starch), and 1 g of lightanhydrous silicic acid (YKF) were placed in a fluidized bed granulatingdryer (Powrex Co., LAB-1 type), and 139 g of purified water containing18 g of D-mannitol and 0.6 g of yellow ferric oxide (Anstead) wassprayed, followed by granulating and drying processes, to give granules.

[0111] To 347 g of the granules, 25 g of crospovidone (ISP Inc.), 1 g oflight anhydrous silicic acid, 10 g of magnesium stearate (Taihei KagakuSangyo Co. Ltd.), and 1 g of aspartame (Ajinomoto Co. Ltd.) were added,to give a mixed powder.

[0112] This mixed powder was tabletted into tablets weighing 250 mg each(Kikusui Seisakusho, Correct 12HUK, tablet size of 9.5 mmφ, compressionpressure of 9.8 kN (1 ton)/cm²)

Example 2

[0113] A 180 g portion of manidipine hydrochloride, 495 g of D-mannitol(Merck Co.: 1.05980, mean particle diameter of 45 μm), 225 g of cornstarch, 112.5 g of crystalline cellulose, 2 g of light anhydrous silicicacid, and 56.3 g of crospovidone were placed in a fluidized bedgranulating dryer (Powrex Co., FD-3SN type), and 540 g of purified watercontaining 42.8 g of D-mannitol and 1.4 g of yellow ferric oxide wassprayed, followed by granulating and drying processes, to give granulesA.

[0114] Separately, 872.1 g of D-mannitol (Towa Chemical Industry Co.,Ltd.: Mannit S), 112.5 g of crystalline cellulose, and 56.3 g ofcrospovidone were placed in a fluidized bed granulating dryer (PowrexCo., FD-3SN type), and 540 g of purified water containing 36.2 g ofD-mannitol and 1.4 g of yellow ferric oxide was sprayed, followed bygranulating and drying processes, to give granules B.

[0115] A 1003 g portion of granules A, 971 g of granules B, 6.3 g oflight anhydrous silicic acid, 4.1 g of aspartame, and 41 g of magnesiumstearate were mixed.

[0116] This mixed powder was tabletted into tablets weighing 250 mg each(Kikusui Seisakusho, Correct 12HUK, tablet size of 9.5 mmφ, compressionpressure of 4.9, 9.8, and 19.6 kN /cm²).

Example 3

[0117] A 90 g portion of manidipine hydrochloride, 416 g of D-mannitol(Merck Co.: 1.05980, mean particle diameter of 45 μm), 189 g of cornstarch, 94.5 g of crystalline cellulose, 1.7 g of light anhydroussilicic acid, and 47.3 g of crospovidone were placed in a fluidized bedgranulating dryer (Powrex Co., FD-3SN type), and 423 g of purified watercontaining 33.5 g of D-mannitol and 0.4 g of yellow ferric oxide wassprayed, followed by granulating and drying processes, to give granulesC.

[0118] Separately, 884 g of D-mannitol (Towa Chemical Industry Co.,Ltd.: Mannit S), 105 g of crystalline cellulose, and 52.5 g ofcrospovidone were placed in a fluidized bed granulating dryer (PowrexCo., FD-3SN type), and 540 g of purified water containing 35.7 g ofD-mannitol and 0.4 g of yellow ferric oxide was sprayed, followed bygranulating and drying processes, to give granules D.

[0119] A 760 g portion of granules C, 845 g of granules D, 5.1 g oflight anhydrous silicic acid, 3.9 g of aspartame, and 33 g of magnesiumstearate were mixed.

[0120] This mixed powder was tabletted into tablets weighing 210 mg each(Kikusui Seisakusho, Correct 12HUK, tablet size of 9.0 mmφ, compressionpressure of 9.8 kN/cm²).

Example 4

[0121] An 80 g portion of manidipine hydrochloride, 220 g of-D-mannitol(Merck Co.: 1.05980, mean particle diameter of 45 μm), 100 g of cornstarch, and 1.2 g of light anhydrous silicic acid were placed in afluidized bed granulating dryer (Powrex Co., LAB-1 type), and 200 g ofpurified water containing 6 g of hydroxypropylcellulose (Nippon SodaCo., Ltd.) and 0.4 g of yellow ferric oxide was sprayed, followed bygranulating and drying processes, to give granules E.

[0122] Separately, 400.5 g of D-mannitol (Towa Chemical Industry Co.,Ltd.: Mannit S), and 100 g of crystalline cellulose were placed in afluidized bed granulating dryer (Powrex Co., LAB-1 type), and 180 g ofpurified water containing 16.1 g of D-mannitol and 0.8 g of yellowferric oxide was sprayed, followed by granulating and drying processes,to give granules F.

[0123] A 203.8 g portion of granules E, 258.8 g of granules F, 25 g ofcrospovidone, 1.4 g of light anhydrous silicic acid, 1 g of aspartame,and 10 g of magnesium stearate were mixed.

[0124] This mixed powder was tabletted into tablets weighing 250 mg each(Kikusui Seisakusho, Correct 12HUK, tablet size of 9.5 mmφ, compressionpressure of 9.8 kN/cm²).

Example 5

[0125] A 289 g portion of D-mannitol (Towa Chemical Industry Co., Ltd.:Mannit S), 40 g of crystalline cellulose, 40 g of corn starch, and 1.2 gof light anhydrous silicic acid were placed in a fluidized bedgranulating dryer (Powrex Co., LAB-1 type), and 120 g of purified watercontaining 0.4 g of voglibose and 10 mg of Food Yellow No.5 was sprayed,followed by granulating and drying processes, to give granules.

[0126] To 296 g of the granules, 16 g of crospovidone, 0.32 g of lightanhydrous silicic acid, 6.4 g of magnesium stearate, and 0.96 g ofaspartame were added, to give a mixed powder.

[0127] This mixed powder was tabletted into tablets weighing 200 mg each(Kikusui Seisakusho, Correct 12HUK, tablet size of 9.0 mmφ, compressionpressure of 9.8 kN/cm²).

Example 6

[0128] A 16 g portion of candesartan cilexetil, 273 g of D-mannitol(Towa Chemical Industry Co., Ltd.: Mannit S), 40 g of crystallinecellulose, 40 g of corn starch, and 1.2 g of light anhydrous silicicacid were placed in a fluidized bed granulating dryer (Powrex Co., LAB-1type), and 120 g of purified water was sprayed, followed by granulatingand drying processes, to give granules.

[0129] To 296 g of the granules, 16 g of crospovidone, 0.32 g of lightanhydrous silicic acid, 6.4 g of magnesium stearate, and 0.96 g ofaspartame were added, to give a mixed powder.

[0130] This mixed powder was tabletted into tablets weighing 200 mg each(Kikusui Seisakusho, Correct 12HUK, tablet size of 9.0 mmφ, compressionpressure of 9.8 kN/cm²).

Example 7

[0131] A 660 mg portion of pioglitazone hydrochloride, 2670 mg ofD-mannitol (Towa Chemical Industry Co., Ltd.: Mannit S), 500 mg ofcrystalline cellulose, 500 mg of corn starch, 500 mg of crospovidone, 20mg of light anhydrous silicic acid, 100 mg of magnesium stearate, and 50mg of aspartame were mixed in a tablet bottle.

[0132] This mixed powder was tabletted into tablets weighing 250 mg each(Shimadzu Corporation, Universal testing machine UH-10A, tablet size of9.5 mmφ, compression pressure of 9.8 kN/cm²).

Example 8

[0133] A 900 g portion of manidipine hydrochloride, 1374.8 g ofgranulated lactose powder (Freund Sangyo.: Dilactose S, mean particlediameter of 80 μm), 301.5 g of crospovidone, and 211.5 g of corn starch(Japan Corn Starch) were placed in a fluidized bed granulating dryer(Fuji Sangyo Co., Ltd., FD-5S type), and 4500 g of purified watercontaining 225 g of hydroxypropylcellulose (Nippon Soda Co., Ltd.) and2.3 g of yellow ferric oxide was sprayed, followed by granulating anddrying processes, to give granules G. The granules G were sized at thescreen size (1.0 mmφ) by a power mill (Showa Kagaku Kikai Kosakusho,P-3), to give sized granules G.

[0134] Separately, 2856 g of D-mannitol (Towa Chemical Industry Co.,Ltd.: Mannit S), 1650 g of D-mannitol (Merck Co.: 1.05980), and 249 g ofcrospovidone were placed in a fluidized bed granulating dryer (FujiSangyo Co., Ltd., FD-5S type), and 1500 g of purified water containing150 g of D-mannitol (Towa Chemical Industry Co., Ltd.: Mannit S), 7.5 gof yellow ferric oxide, and 37.5 g of anhydrous citric acid was sprayed,followed by granulating and drying processes, to give granules H. Thegranules G were sized at the screen size (1.0 mm) by a power mill, togive sized granules H.

[0135] A 737 g portion of sized granules G, 1815 g of sized granules H,151.3 g of crystalline cellulose, 5.5 g of aspartame, and 41.3 g ofmagnesium stearate were mixed. This mixed powder was tabletted intotablets weighing 250 mg each (Kikusui Seisakusho, Correct 12HUK, tabletsize of 9.5 mmφ, compression pressure of 7.4 kN /cm²).

Example 9

[0136] A 44 g portion of manidipine hydrochloride, 442.4 g of trehalose(Asahi Chemical Industry Co., Ltd.: Trehalose P, mean particle diameterof 44 μm), and 33 g of crospovidone were placed in a fluidized bedgranulating dryer (Powrex Co., LAB-1 type), and 231 g of purified watercontaining 11 g of hydroxypropylcellulose was sprayed, followed bygranulating and drying processes, to give granules.

[0137] A 459.4 g portion of the granules, 27.2 g of crystallinecellulose, 1.0 g of aspartame, and 7.4 g of magnesium stearate weremixed.

[0138] This mixed powder was tabletted into tablets weighing 250 mg each(Kikusui Seisakusho, Correct 19KAWC, tablet size of 9.5 mmφ, compressionpressure of 2.9 kN/cm²).

Example 10

[0139] Trehalose (Asahi Chemical Industry Co., Ltd.: Trehalose G, meanparticle diameter of 346 μm) was pulverized with a power mill (ShowaKagaku Kikai Kosakusho, P-3) at the screen size (0.5 mmφ), to give apowder with the mean particle diameter of 185 μm.

[0140] This pulverized trehalose was used in place of the trehalose inExample 9, and processed under the same conditions as those in Example9, to give tablets.

Example 11

[0141] Erythritol (Nikkenn Chemicals Co., Ltd.: mean particle diameterof 474 μm) was pulverized with a power mill (Showa Kagaku KikaiKosakusho, P-3) at the screen size (0.5 mmφ), to give a powder with themean particle diameter of 178 μm.

[0142] This pulverized erythritol was used in place of the trehalose inExample 9, and processed under the same conditions as those in Example9, to give tablets. (compression pressure 7.4 kN/cm²)

Example 12

[0143] Xylitol (Towa Chemical Industry Co., Ltd.: Xylit XC, meanparticle diameter of 363 μm) was pulverized with a power mill (ShowaKagaku Kikai Kosakusho, P-3) at the screen size (0.5 mmφ), to give apowder with the mean particle diameter of 135 μm.

[0144] A 50 g portion of manidipine hydrochloride, the pulverizedxylitol, 37.5 g of crospovidone, 15.6 g of crystalline cellulose, and9.4 g of magnesium stearate were mixed.

[0145] This mixed powder was tabletted into tablets weighing 250 mg each(Shimadzu Corporation, Universal testing machine UH-10A, tablet size of9.5 mmφ, compression pressure of 14.7 kN/cm²).

Example 13

[0146] A 50 g portion of manidipine hydrochloride, maltitol (LESYS ofTowa Chemical Industry Co., Ltd., mean particle diameter of 181 μm),37.5 g of crospovidone, 15.6 g of crystalline cellulose, and 9.4 g ofmagnesium stearate were mixed.

[0147] This mixed powder was tabletted into tablets weighing 250 mg each(Shimadzu Corporation, Universal testing machine UH-10A, tablet size of9.5 mmφ, compression pressure of 9.8 kN/cm²). Example 14

[0148] Erythritol (Nikkenn Chemicals Co., Ltd.: mean particle diameterof 474 μm) was pulverized with a jet mill (Nippon Pneumatic MFG Co.,Ltd., PJM-100SP), to give a powder with the mean particle diameter of 75μm.

[0149] This pulverized erythritol was used in place of the trehalose inExample 9, and processed under the same conditions as those in Example9, to give tablets.

Example 15

[0150] Sorbitol (Sorbitol DP-50M of Towa Chemical Industry Co., Ltd.,mean particle diameter of 172 μm) was pulverized with a jet mill (NipponPneumatic MFG Co., Ltd., PJM-100SP), to give a powder with the meanparticle diameter of 43 μm.

[0151] A 25 g portion of manidipine hydrochloride, the pulverizedsorbitol, 18.8 g of crospovidone, 7.8 g of crystalline cellulose, and4.7 g of magnesium stearate were mixed.

[0152] This mixed powder was tabletted into tablets weighing 125 mg each(Shimadzu Corporation, Universal testing machine UH-10A, tablet size-of8.5 mmφ, compression pressure of 2.9 kN/cm²).

Comparative Example 1

[0153] D-Mannitol with the mean particle diameter of 21 μm (Merck Co.:1.05988) was used in place of the D-mannitol in Example 1, and processedunder the same conditions as those in Example 1, to give tablets.

Comparative Example 2

[0154] D-Mannitol with the mean particle diameter of 21 μm (Merck Co.:1.05988) was used in place of the D-mannitol in Example 5, and processedunder the same conditions as those in Example 5, to give tablets.

Comparative Example 3

[0155] Trehalose (Asahi Chemical Industry Co., Ltd.: Trehalose G) waspulverized with the atomizer (Fuji Paudal Co., Ltd., KII-2), to give apowder with the mean particle diameter of 19 μm.

[0156] This pulverized trehalose was used in place of the trehalose inExample 9, and processed under the same conditions as those in Example9, to give tablets.

[0157] The results of measurement of the hardness and the intraoraldisintegration time of the tablets obtained in the Examples andComparative Examples by the above-mentioned test methods, and theresults of evaluation of productivity based on the observation offluidity, binding property, and adhesion of powder to the surface of thepunch during production of tablets are summarized in Table 1. TABLE 1Productivity, hardness, and intraoral disintegration time of tabletsIntraoral Tabletting Fluidity Adhesion disintegration pressure duringBinding to Hardness time (kN/cm²) tabletting property punch (N) (second)Example 1 9.8 good absent absent 37 25 Example 2 4.9 good absent absent17 17 9.8 good absent absent 39 16 19.6 good absent absent 50 20 Example3 9.8 good absent absent 24 17 Example 4 9.8 good absent absent 25 24Example 5 9.8 good absent absent 26 19 Example 6 9.8 good absent absent26 13 Example 7 9.8 good absent absent 33 25 Example 8 7.4 good absentabsent 29 22 Example 9 2.9 good absent absent 21 52 Example 10 2.9 goodabsent absent 16 43 Example 11 7.4 good absent absent 36 31 Example 1214.7 good absent absent 16 61 Example 13 9.8 good absent absent 21 51Example 14 2.9 good absent absent 17 38 Example 15 2.9 good absentabsent 16 67 Comparative 9.8 insufficient present present 49 26 Example1 Comparative 9.8 insufficient present present 33 21 Example 2Comparative 2.9 insufficient present present 25 36 Example 3

Industrial Applicability

[0158] Quickly disintegrating solid preparations, preferably intraorallyquickly disintegrating solid preparations, more preferably intraorallyquickly disintegrating tablets of the invention obtained by theprocesses described above are quickly disintegrated in the oral cavityand have suitable hardness. They are excellent also in productivity.

1. A quickly disintegrating solid preparation comprising a) an activeingredient, b) a saccharide or sugar alcohol with the mean particlediameter of 30 μm to 300 μm, c) a disintegrating agent, and d) acellulose compound.
 2. The preparation according to claim 1, which is anintraorally quickly disintegrating solid preparation.
 3. The preparationaccording to claim 1, which is a tablet preparation.
 4. The preparationaccording to claim 1, which contains 40 to 95 parts of a saccharide orsugar alcohol per 100 parts of the solid preparation by weight.
 5. Thepreparation according to claim 1, which contains 0.5 to 15 parts of adisintegrating agent per 100 parts of the solid preparation by weight.6. The preparation according to claim 1, which contains 0.5 to 40 partsof a cellulose compound per 100 parts of the solid preparation byweight.
 7. The preparation according to claim 1, wherein the saccharideis one or more saccharides selected from the group consisting ofglucose, fructose, lactose, sucrose, and trehalose.
 8. The preparationaccording to claim 1, wherein the saccharide is lactose.
 9. Thepreparation according to claim 1, wherein the sugar alcohol is one ormore sugar alcohols selected from the group consisting of D-mannitol,erythritol, xylitol, maltitol, and sorbitol.
 10. The preparationaccording to claim 1, wherein the sugar alcohol is D-mannitol.
 11. Thepreparation according to claim 1, characterized in that D-mannitol withthe mean particle diameter of 30 μm to 300 μm is used as the saccharideor sugar alcohol with the mean particle diameter of 30 μm to 300 μm. 12.The preparation according to claim 1, wherein the disintegrating agentis one or more disintegrating agents selected from the group consistingof carmellose calcium, carboxymethylstarch sodium, croscarmellosesodium, and crospovidone.
 13. The preparation according to claim 1,wherein the cellulose compound is one or more cellulose compoundsselected from the group consisting of crystalline cellulose, powdercellulose, low substituted hydroxypropylcellulose, and carmellose. 14.The preparation according to claim 1, wherein the active ingredient ismanidipine hydrochloride.
 15. The preparation according to claim 1,wherein the active ingredient is voglibose.
 16. The preparationaccording to claim 1, wherein the active ingredient is candesartancilexetil.
 17. The preparation according to claim 1, wherein the activeingredient is pioglitazone hydrochloride.
 18. The procedure forproduction of the preparation according to claim 1, characterized inthat a mixture containing a) an active ingredient, b) a saccharide orsugar alcohol with the mean particle diameter of 30 μm to 300 μm, c) adisintegrating agent, and d) a cellulose compound is subjected tocompression molding.
 19. A quickly disintegrating solid preparationcomprising a) an active ingredient, b-1) a saccharide or sugar alcoholwith the mean particle diameter of 5 μm to below 90 μm, b-2) asaccharide or sugar alcohol with the mean particle diameter of 90 μm to500 μm, c) a disintegrating agent, and d) a cellulose compound.
 20. Thepreparation according to claim 19, which contains 0.1 to 10 parts of theingredient b-2) per 1 part of the ingredient b-1) by weight.
 21. Thepreparation according to claim 19, characterized in that a mixture ofthe ingredient b-1) and the ingredient b-2) is used as the ingredientb-1) and the ingredient b-2).
 22. The preparation according to claim 21,wherein the mean particle diameter of the mixture is 30 μm to 300 μm.23. The preparation according to claim 19, wherein the-mean particlediameter of the ingredient b-1) is 30 μm to below 90 μm.
 24. Thepreparation according to claim 19, wherein the mean particle diameter ofthe ingredient b-1) is 35 μm to 80 μm.
 25. The preparation according toclaim 19, wherein the mean particle diameter of the ingredient b-2) is90 μm to 300 μm.
 26. The preparation according to claim 19, wherein themean particle diameter of the ingredient b-2) is 90 μm to 200 μm. 27.The preparation according to claim 19, wherein the saccharide is one ormore saccharides selected from the group consisting of glucose,fructose, lactose, sucrose, and trehalose.
 28. The preparation accordingto claim 19, wherein the sugar is lactose.
 29. The preparation accordingto claim 19, wherein the sugar alcohol is one or more sugar alcoholsselected from the group consisting of D-mannitol, erythritol, xylitol,maltitol, and sorbitol.
 30. The preparation according to claim 19,wherein the sugar alcohol is D-mannitol.
 31. The preparation accordingto claim 19, characterized in that D-mannitol with the mean particlediameter of 30 μm to below 90 μm and D-mannitol with the mean particlediameter of 90 μm to 300 μm are used as the ingredient b-1) and theingredient b-2), respectively.
 32. The procedure for production of thepreparation according to claim 19, characterized in that a mixturecontaining a) an active ingredient, b-1) a saccharide or sugar alcoholwith the mean particle diameter of 5 μm to below 90 μm, b-2) asaccharide or sugar alcohol with the mean particle diameter of 90 μm to500 μm, c) a disintegrating agent, and d) a cellulose compound issubjected to compression molding.